The present invention relates to the use of piperazinyl-heterocyclic compounds of the formula I, as defined below, for the treatment of glaucoma and ischemic retinopathy.
The piperazinyl-heterocyclic compounds of formula I and their utility for the treatment of psychotic disorders, including schizophrenia, are referred to in U.S. Pat. Nos. 4,831,031 and 4,883,795, which issued, respectively, on May 16, 1989 and Nov. 28, 1989. The ulitity of such compounds for the treatment of obsessive-compulsive disorder and Tourette""s syndrome is referred to in U.S. Provisional Application 60/057,987, which was filed on Sep. 5, 1997. The utility of such compounds for the treatment of certain psychiatric disorders that have as symptoms behavioral disturbances (e.g., anxiety, bipolar disorder, major depressive disorder, autistic disorder, conduct disorder, dementias including dementias associated with Alzheimer""s disease, and drug induced and neurodegeneration based dyskinesias is referred to in U.S. Provisional Application 60/068,069, which was filed on Dec. 18, 1997. All of the foregoing patents and patent applications are assigned in common with the present application.
Current treatments for glaucoma include the use of beta-adrenergic antagonists such as timolol and betaxolol, which, like the compounds administered in the methods of this invention (i.e., compounds of the formula I, as defined below), are effective in reducing intraocular pressure. The compounds of formula I, however, do not exhibit beta-adrenergic blocking activity and thus do not have associated with them the negative cardiac side effects that are associated with beta-adrenergic blockers (e., systemic absorption leading to slowing of the heart).
Methods of preparing the novel compounds of the formula I and their pharmaceutically acceptable salts are referred to in each of the following: U.S. Pat. Nos. 4, 831,031 and 4,883,795, referred to above, and in U.S. Pat. Nos. 5,206,366 and 5,338,846, which were issued, respectively, on Apr. 27, 1993 and Aug. 16, 1994. All of the foregoing patents are assigned in common with the present application and incorporated herein by reference in their entireties.
The present invention also relates to a method of treating a disorder or condition that can be treated by decreasing intraocular pressure in a mammal, including a human, comprising administering to said mammal a therapeutically effective amount of a compound of the formula

or a pharmaceutically acceptable acid addition salt thereof, wherein
Ar is benzoisothiazolyl or an oxide or dioxide thereof each optionally substituted by one fluoro, chloro, trifluoromethyl, methoxy, cyano or nitro; naphthyl optionally substituted by fluoro, chloro, trifluoromethyl, methoxy, cyano or nitro; quinolyl; 6-hydroxy-8-quinolyl; isoquinolyl; quinazolyl; benzothiazolyl; benzothiadiazolyl; benzotriazolyl; benzoxazolyl; benzoxazolonyl; indolyl; indanyl optionally substituted by one or two fluoro; 3-indazolyl optionally substituted by 1-trifluoromethylphenyl; or phthalazinyl;
n is 1 or 2; and
X and Y together with the phenyl to which they are attached form a cyclic ring system selected from quinolyl; 2-hydroxyquinolyl; benzothiazolyl; 2-aminobenzothiazolyl; benzoisothiazolyl; indazolyl; 2-hydroxyindazolyl; indolyl; oxindolyl optionally substituted by spirocycloalkyl wherein said cycloalkyl moiety contains from 4 to 7 carbon atoms, or by one to three of (C1-C3)alkyl, or by one of chloro, fluoro or phenyl wherein said phenyl is optionally substituted by one chloro or fluoro; benzoxazolyl; 2-aminobenzoxazolyl; benzoxazolonyl; 2-aminobenzoxazolinyl; benzothiazolonyl; benzoimidazolonyl; and benzotriazolyl.
The present invention also relates to a method for treating glaucoma (e.g., open angle glaucoma, wide angle glaucoma, aphakic glaucoma and secondary glaucoma) or ischemic retinopathy (i.e., ischemic retinal degeneration) in a mammal, including a human, comprising administering to said mammal a therapeutically effective amount of compound of the formula 
or a pharmaceutically acceptable acid addition salt thereof, wherein
Ar is benzoisothiazolyl or an oxide or dioxide thereof each optionally substituted by one fluoro, chloro, trifluoromethyl, methoxy, cyano or nitro; naphthyl optionally substituted by fluoro, chloro, trifluoromethyl, methoxy, cyano or nitro; quinolyl; 6-hydroxy-8-quinolyl; isoquinolyl; quinazolyl; benzothiazolyl; benzothiadiazolyl; benzotriazolyl; benzoxazolyl; benzoxazolonyl; indolyl; indanyl optionally substituted by one or two fluoro; 3-indazolyl optionally substituted by 1-trifluoromethylphenyl; or phthalazinyl;
n is 1 or 2; and
X and Y together with the phenyl to which they are attached form a cyclic ring system selected from quinolyl; 2-hydroxyquinolyl; benzothiazolyl; 2-aminobenzothiazolyl; benzoisothiazolyl; indazolyl; 2-hydroxyindazolyl; indolyl; oxindolyl optionally substituted by spirocycloalkyl wherein said cycloalkyl moiety contains from 4 to 7 carbon atoms, or by one to three of (C1-C3)alkyl, or by one of chloro, fluoro or phenyl wherein said phenyl is optionally substituted by one chloro or fluoro; benzoxazolyl; 2-aminobenzoxazolyl; benzoxazolonyl; 2-aminobenzoxazolinyl; benzothiazolonyl; benzoimidazolonyl; and benzotriazolyl.
This invention also relates to a method of treating a disorder or condition that can be treated by improving blood flow in the retina of a mammal, including a human, comprising administering to said mammal a therapeutically effective amount of a compound of the formula

or a pharmaceutically acceptable acid addition salt thereof, wherein
Ar is benzoisothiazolyl or an oxide or dioxide thereof each optionally substituted by one fluoro, chloro, trifluoromethyl, methoxy, cyano or nitro; naphthyl optionally substituted by fluoro, chloro, trifluoromethyl, methoxy, cyano or nitro; quinolyl; 6-hydroxy-8-quinolyl; isoquinolyl; quinazolyl; benzothiazolyl; benzothiadiazolyl; benzotriazolyl; benzoxazolyl; benzoxazolonyl; indolyl; indanyl optionally substituted by one or two fluoro; 3-indazolyl optionally substituted by 1-trifluoromethylphenyl; or phthalazinyl;
n is 1 or 2; and
X and Y together with the phenyl to which they are attached form a cyclic ring system selected from quinolyl; 2-hydroxyquinolyl; benzothiazolyl; 2-aminobenzothiazolyl; benzoisothiazolyl; indazolyl; 2-hydroxyindazolyl; indolyl; oxindolyl optionally substituted by spirocycloalkyl wherein said cycloalkyl moiety contains from 4 to 7 carbon atoms, or by one to three of (C1-C3)alkyl, or by one of chloro, fluoro or phenyl wherein said phenyl is optionally substituted by one chloro or fluoro; benzoxazolyl; 2-aminobenzoxazolyl; benzoxazolonyl; 2-aminobenzoxazolinyl; benzothiazolonyl; benzoimidazolonyl; and benzotriazolyl.
The term xe2x80x9ctreatingxe2x80x9d, as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorders or condition. The term xe2x80x9ctreatmentxe2x80x9d, as used herein, refers to the act of treating, as xe2x80x9ctreatingxe2x80x9d is defined immediately above.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d, as used herein, refers to an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating the disorder or condition for which such compound or salt is being administered.
A preferred embodiment of this invention relates to any of the inventive methods described above wherein the compound of formula I or pharmaceutically acceptable salt is administered is for the treatment of glaucoma.
Another preferred embodiment of this invention relates to any of the inventive methods described above wherein the compound of formula I or pharmaceutically acceptable salt is administered for the treatment of ischemic retinopathy.
Another preferred embodiment of this invention relates to any of the inventive methods described above wherein the compound of formula I or pharmaceutically acceptable salt that is administered is one wherein Ar is benzoisothiazolyl and n is 1.
Another preferred embodiment of this invention relates to any of the inventive methods described above wherein the compound of formula I or pharmaceutically acceptable salt that is administered is one wherein X and Y, together with the phenyl moiety to which they are attached, form an oxindole group that is optionally substituted by chloro, fluoro or phenyl.
Another preferred embodiment of this invention relates to any of the inventive methods described above wherein the compound of formula I or pharmaceutically acceptable salt that is administered is one wherein Ar is naphthyl and n is 1.
Another preferred embodiment of this invention relates to any of the inventive methods described above wherein the compound of formula I or pharmaceutically acceptable salt that is administered is ziprasidone (5-[2-{4-(1,2-benzisothiazol-3-yl)-1-piperazinyl}ethyl]-6-chloro-1,3-dihydro-2H-indole-2-one) or a pharmaceutically acceptable salt thereof.
The piperazinyl-heterocyclic compounds of formula I can be prepared by one or more of the synthetic methods described and referred to in U.S. Pat. Nos. 4,831,031; 4,883,795; 5,206,366 and 5,338,846. A preferred method of making such compounds is referred to in U.S. Pat. No. 5,338,846.
The compounds of formula I may be prepared by reacting piperazines of the formula II with compounds of the formula III as follows: 
wherein Hal is fluoro, chloro, bromo or iodo. This coupling reaction is generally conducted in a polar solvent such as a lower alcohol (e.g., ethanol), dimethylformamide or methylisobutylketone in the presence of a weak base such as a tertiary amine base (e.g., triethylamine or diisopropylethylamine). Preferably, the reaction is also carried out in the presence of a catalytic amount of sodium iodide, and in the presence of a neutralizing agent for hydrochloride such as sodium carbonate. This reaction is preferably carried out at the reflux temperature of the solvent.
The piperazine derivatives of formula II may be prepared by methods well known in the art. For example, such compounds can be prepared by reacting an aryl halide of the formula ArHal, wherein Ar is as defined above and Hal is fluoro, chloro, bromo or iodo, with piperazine in a hydrocarbon solvent such as toluene, at a temperature from about room temperature to about the reflux temperature, for about a half hour to about 24 hours. Alternatively, compounds of the formula II may be prepared by heating an amino substituted aryl compound of the formula ArNH2, wherein Ar is as defined above, with a compound of the formula VI 
wherein G is a leaving group such as chloro, bromo or mesylate and R1 is a group such as benzyl or COOR2 wherein R2 is benzyl or (C1-C6) alkyl, which can be subsequently removed to form the piperizine ring that is attached to the aryl group Ar.
The compounds of formula III may also be prepared by well known methods. For instance, they can be prepared by reacting a haloacetic acid or halobutyric acid, wherein the halogen substituent is fluoro, chloro, bromo or iodo, with a compound of the formula IV as follows: 
wherein X and Y are as defined above and m is 1 or 3. The resulting compounds of the formula V are then reduced, e.g., with triethylsilane and trifluoroacetic acid in a nitrogen atmosphere, to form compounds of the formula III.
When Ar is the oxide or dioxide of benzoisothiazolyl, the corresponding benzoisothiazolyl compound is oxidized under acid conditions at low temperatures. The acid used is preferably a mixture of sulphuric acid and nitric acid.
Preferably, compounds of the formula I are prepared by reacting a piperazine salt of the formula 
wherein Z is fluoro, chloro, bromo, iodo, methanesulfonate, trifluoromethanesulfonate, or trifluoroacetate, and Ar is as defined above, with an alkyl halide containing a compound of the formula 
wherein n, X and Y are as defined above and Hal is fluoro, chloro, bromo or iodo, in water with an excess of reagent to neutralize the hydrohalic acid, heating the mixture under conditions which are suitable to effect the coupling of said piperazine salt with said alkyl halide containing compound, and, if desired, preparing the corresponding pharmaceutically acceptable acid addition salt. Preferably, the mixture is heated to about the reflux temperature. Especially preferably, the compound of formula I is reacted with aqueous hydrochloric acid to form a hydrochloride monohydrate.
The pharmaceutically acceptable acid addition salts of the compounds of formula I are prepared in a conventional manner by treating a solution or suspension of the free base (I) with about one chemical equivalent of a pharmaceutically acceptable acid. Conventional concentration and recrystallization techniques are employed in isolating the salts. Illustrative of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic such as methanesulfonic, benzenesulfonic, and related acids.
Compounds of formula I, and their pharmaceutically acceptable salts (referred to collectively, hereinafter, as xe2x80x9cthe active compounds of this inventionxe2x80x9d), can be administered to a human subject either alone, or, preferably, in combination with pharmaceutically-acceptable carriers or diluents, in a pharmaceutical practice. Such compounds can be administered orally or topically (e.g., in the form of eye drops, ointments or lotions). In such topical pharmaceutical dosage forms, the active agent will generally be present in a concentration of about 0.05 to 1.0 weight percent, preferably in a concentration of about 0.12 to about 0.5 weight percent. The weight percent of the active agent will depend on such factors as the solubility of the active component, the dosage contemplated and the precise route of administration.
For oral use, the active compounds of this invention can be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which can be used include lactose and corn starch, and lubricating agents, such as magnesium stearate, can be added. For oral administration in capsule form, useful diluents are lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient can be combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents can be added.
When an active compound of this invention is to be used in a human subject to treat glaucoma or icshemic retinopathy, the daily dosage will normally be determined by the prescribing physician. Moreover, the dosage will vary according to the age, weight and response of the individual patient as well as the severity of the patient""s symptoms. However, in most instances, an effective amount for treating such disorders will be a daily dosage in the range from about 0.025 mg per day to about 20 mg per day, and preferably from 0.5 mg per day to about 8.0 mg per day, in single or divided doses, orally or topically. In some instances it may be necessary to use dosages outside these limits.
The active compounds of this invention may also be administered in combination with one or more other active agents that are anti-glaucoma agents, either as part of the same pharmaceutical composition or in a separate pharmaceutical composition as part of the same dose regimen. Examples of anti-glaucoma agents that can be used in combination with the active compounds of this invention are beta-adrenergic receptor antagonists such as betaxolol and timolol, and carbonic anhydrase inhibitors such as acetazolamide and dorzolamide.
The receptor binding and neurotransmitter uptake inhibition profile for ziprasidone, 5-(2-(4-(1,2-benzisothiazol-3-yl)piperazinyl)ethyl)-6-chlorooxindole hydrochloride, was described in The Journal of Pharmacology and Experimental Therapeutics, 275, 101-113 (1995), which is incorporated herein by reference in its entirety. A summary of its affinity (pKi) for various receptors in the central nervous system tissue is presented in Table 1.
Ziprasidone has been found effective for the following indications: psychotic disorders, acute mania, anxiety states, schizophrenia, bipolar disorder, Alzheimer""s disease (delusions, delirium), depression and psychotic disorders.